FIFRA Scientific Advisory Panel M

New High Throughput Methods to Esti

Chemical Exposure

FIFRA Scientific Advisory Panel M

New High Throughput Methods to Esti

Chemical Exposure

Arlington, VA

July 29 ‐ August 1, 2014

Arlington, VA

July 29 ‐ August 1, 2014
EPA’s Endocrine Disruptor

Screening Program

EPA’s Endocrine Disruptor

Screening Program

Presented by David Dix, Ph.D.

Director, Office of Science Coordination and Pol

Office of Chemical Safety and Pollution Prevent

Presented by David Dix, Ph.D.

Director, Office of Science Coordination and Pol

Office of Chemical Safety and Pollution Prevent
1996 Legislative Mandate

1996 Federal Food, Drug and Cosmetic Act, section 408(p)

Requires the U. S. EPA to develop a screening program usin

appropriate validated test systems and other scientifically 

methods to determine whether certain substances may ha

in humans that is similar to an effect produced by a natura

occurring estrogen, or other such endocrine effect as the

Administrator may designate.

1996 Safe Drinking Water Act Amendments, section 1457

Testing of chemical substances that may be found in source

drinking water, if substantial human populations may be

exposed.
EDSP Implementation

 EDSP List 2 Chemicals

• Draft EDSP List 2 chemicals for Tier 1 screening 

(2010)

• EPA issued revised EDSP List 2 with 109 chemica

‐ Selection based on registration review schedule of 41 p

chemicals and 68 drinking water contaminants

EDSP Chemical Universe

10,000 chemicals

(FIFRA & SDWA)

EDSP List 2

109 Chemicals

EDSP List 1

52 Chemicals
Evolution of the EDSP

 Based on current pace it could take decades to 

all 10,000 chemicals for potential to interact w

endocrine system

 Recent advances in computational toxicology h

important “evolutionary turning point” and an

accelerated pace of screening and testing

 To address thousands of chemicals for potentia

interact with the endocrine system, we must

implement a more strategic approach to priori

chemicals for targeted screening
Screening and Prioritizatio

 ToxCast

• Expanding use of CompTox (Phys‐

chem properties, QSARS, etc.) to

support screening andprioritization

• Transparent and collaborative

 ExpoCast

• Rapid exposure estimation based

on readily available chemical use

and production data

• Use toxicokinetics to bridge in

vitro, concentration‐based ToxCastdata to in vivo, dose‐based

Exposures from ExpoCast

ToxCast

ExpoCast
New High Throughput Methods 

Estimate Chemical Exposure

New High Throughput Methods 

Estimate Chemical Exposure

Presented by Alan Dixon

Endocrine Disruptor Screening Program

Office of Science Coordination & Policy

Office of Chemical Safety and Pollution Prevent

Presented by Alan Dixon

Endocrine Disruptor Screening Program

Office of Science Coordination & Policy

Office of Chemical Safety and Pollution Prevent
Introduction

Exposure Estimation with

ExpoCast Research

High Throughput

Toxicokinetics (HTTK) and

Reverse Toxicokinetics (RTK)

Ongoing Research

Future App

Presentation Roadmap
High Throughput Exposure Methods a

Reverse Toxicokinetics for Screening and Prio

 HTE Methods and RTK

• Rapid exposure estimation based on

readily available chemical use and

production data

• Use toxicokinetics to bridge in vitro,

concentration‐based ToxCast data toin vivo, dose‐based Exposures from

ExpoCast

RTK

ToxCast

HTE

Methods

 ToxCast

• Expanding use of CompTox (Phys‐

chem properties, QSARS, etc.) tosupport screening and prioritization

• Transparent and collaborative

This SAP
Using Exposure for Setting EDSP Prior

 EDSTAC recommendation (August 1998)“Data resulting from HTPS [bioactivity/hazard] will be combined with exposure‐rela

and with any other effects‐related information that is available, for each chemical fo

setting priorities for T1S”

 January 2013 SAP recommendation (Meeting minutes page 24)“A number of approaches were identified by the Panel to potentially improve comp

prioritization efforts. HTP assays could effectively be used to categorize chemicals in 

through the use of a decision tree. Exposure potential could be incorporated into t

prioritize chemicals for further testing...”

 Overall Priority Setting for EDSP Universe

Other chemicals beyond List 1 and List 2 could have higher priority for and testing if bioactivity considerations are joined with exposure consi

integrated approach.
The Need for High Throughput Exposure Esti

 EDSP Universe of Chemicals

• Inventory of approximately 10,000+ Chemicals that EDSP has regu

authority

– Based on current pace of using low‐throughput exposure assessment meth

List 2) it could take decades to prioritize and screen all 10,000 chemicals fo

interact with the endocrine system

– Recent advances in computational exposure estimation could be used to a

pace of estimating exposures from a few chemicals a year to thousands of 

year—a critical step in prioritizing and screening chemicals

10000

67109

176

EDSP Universe List 1 List 2
Fit for Purpose

 What High Throughput Exposure (HTE) IS

• While these High Throughput Exposure exposure estim

methods may

– Not have the temporal and spacial specificity of traditiona

throughput assessments

– May only be within an order of magnitude of traditional lo

throughput assessments

• HTE estimation is “fit” to be used to rank chemicals b

their estimated/predicted exposure.

• That is, HTE exposure estimates are “fit” to discern ch

with higher potential exposure from chemicals with lo

potential exposure.

• This in turn will be considered along with bioactivity t

and screen chemicals for traditional low‐throughput a

methods.
Fit for Purpose (continued)

 What High Throughput Exposure (HTE) 

• The HTE estimation methods presented ar

intended to be precise assessments simila

traditional Low Throughput exposure

assessments, e.g. the exposure assessmen

in OPP’s Registration Review Decisions
Application of Exposure to EDSP Prioriti

Adapted from White Paper: Section 5. Future Ap

Potential Exposure from ExpoCast

mg/kg BW/day

In vitro Bioactivity from ToxCast with

Reverse Toxicokinetics

LowPriority

MedPriority

HigherPriority
Introduction

Exposure Estimation with

ExpoCast Research

High Throughput

Toxicokinetics (HTTK) and

Reverse Toxicokinetics (RTK)

Ongoing Research

Future App

Presentation Roadmap

Human Exposure Estimates• First Generation SEEM• Second Generation SEEM